Mammary secretory carcinoma | |
---|---|
Other names | Secretory carcinoma of the breast |
Specialty | Breast surgery, Surgical oncology |
Complications | Very rare cases may become aggressive cancers |
Usual onset | Adult females, less commonly adult males or female and male children |
Duration | Very slow growing |
Causes | Formation of an ETV6-NTRK3 fusion gene |
Prognosis | good to excellent |
Frequency | rare |
Deaths | rare |
Mammary secretory carcinoma (MSC), also termed secretory carcinoma of the breast, is a rare form of the breast cancers. [1] MSC usually affects women but in a significant percentage of cases also occurs in men and children. [2] Indeed, McDvitt and Stewart first described MSC in 1966 and termed it juvenile breast carcinoma because an increased number of cases were at that time diagnosed in juvenile females. [3] MSC is the most common form of breast cancer in children, [4] representing 80% of childhood breast cancers, [5] although it accounts for less than 0.15% of all breast cancers. [6] (In the pediatric population, about 65% of all breast malignancies are carcinomas. [5] )
In 1980, Tavaosoli and Norris renamed juvenile breast carcinoma as "secretory carcinoma of the breast" based on its characteristic microscopic appearance [7] of having eosinophilic (i.e. red or pink) extracellular secretions when its tissues were stained with the H&E stain. [8] MSC has sometimes been termed secretory carcinoma without reference to its breast cancer location. However, the term secretory carcinoma has also been used to name tumors with the microscopic appearance of MSC that are localized in the salivary glands (now termed mammary analogue secretory carcinoma), [9] thyroid gland (now termed salivary gland–type carcinoma of the thyroid), [10] or skin (now termed secretory carcinoma of the skin or primary cutaneous mammary analog secretory carcinoma). [11] [12] Mammary secretory carcinoma is used here to distinguish it from these formerly termed secretory carcinomas.
MSCs typically develop as ductal breast tumors that have invaded the tissue around their ducts of origin, may have spread to nearby sentinel lymph nodes or axillary lymph nodes but have rarely metastasized (i.e. spread) to distant tissues. [6] They are usually small, slow-growing, painless, [5] well-circumscribed, movable breast masses. [4] MSC tumors typically have distinctive microscopic features and tumor cells that carry a characteristic genetic abnormality that appears to underlie their development and/or progression. [2]
Surgical removal has been considered the mainstay of treatment for localized MSCs tumors. The rare cases of MSC tumors that have metastasized to distal tissues have been treated with chemotherapy and radiation therapy but have shown little to no responses to these treatments. Emerging studies suggest that drug therapy targeted at the genetic abnormality in MSC tumor cells may be a more effective treatment for the latter tumors. [13]
In a review study of 190 individuals diagnosed with MSC, patient ages ranged from 2 to 96 years (median age: 56 years); 5% of cases were aged less than 21 years; the male to female ratio was 1 to 30; the tumors were in the left, right, and both breasts in 103, 85 and 2 cases, respectively; and the tumors were usually located on a breast's left, outer quadrant. [1] (In younger patients, these tumors more often occur beneath the areola, i.e. pigmented region around the breast's nipple. [14] ) In a subgroup of 99 patients on which there was sufficient information, average tumor sizes were 2.3 centimeters (cm.) with 29.3% of these patients evidencing lymph node metastases. [1] This study did not have patients who presented with metastasis to tissues beyond their sentinel lymph nodes. In a review study of 44 individuals with MSC, 41 patients were female and 3 were male; patient ages ranged between 4 and 76 years (median age: 48 years) with 4 patients being adolescents; patient tumor sizes ranged from 1.5 to 10 cm. (mean size: 3.5 cm.) (Individual cases of MSC have had tumor sizes as large as 16 cm. [4] ) and 15 patients presented with lymph node metastases. While none of these patients presented with metastasis beyond sentinel lymph nodes, follow up studies over an average of 93.4 months identified 4 patients with metastases to the bone, 1 patient with metastases to the liver, and 1 patient with unspecified distant metastases. Five of these patients died of their disease. [15]
In a review study 12 female and 2 male patients 8 to 81 years (mean age: 48 years), 8 patients presented with a palpable mass, 4 presented with a mass detected on screening mammography, and 2 patients lacked information on this; 8 tumors were located in the left and 6 in the right breast; and 2 of the 10 patents tested by biopsy had sentinel lymph node metastases. One of these patients presented with distant tissue metastases, 12 re-presented with distant metastasis within 5–240 months of their initial diagnoses and treatments, and one lacked information on this. Eight of these patients died from their disease 7 to 240 months (mean survival time: 74.6 months) after their initial diagnosis, 4 were alive with their disease 7 to 84 months after their initial diagnosis, and 2 had no information on this. The metastases, which often were to multiple sites, were located in the lung (9 cases), liver (4 cases), bone (4 cases), skin (2 cases), kidney (1 case), mediastinum (1 case), pancreas (1 case), and/or lung's pleura (1 case). [8] Rare cases of MSC have presented in individuals who have or had and been treated for papillomatosis of breasts; this benign breast diseases is often associated with other breast carcinomas, the by far most common of which is MSC. [5]
As of 2019, only 6 cases presented with purely in situ (i.e. totally localized tumors that have not invaded tissues outside of the breasts' ducts) tumors (as reported in the English literature). The tumor tissues in all of these cases had at least one area with a papillary microscopic histopathology (see Pathology section). [16]
The microscopic histopathology of H&E-stained MSC tumors generally shows well-circumscribed solid tumors with multiple microcysts [13] and sheets of epithelial cells containing numerous vacuoles in their cytoplasm, signet ring cells (i.e. cells with one large cytoplasmic vacuole termed a globule), and extracellular droplet-like secretions resembling the cytoplasmic globules. [2] The sheets of cells are separated by bands of connective tissue. [5] In occasional cases, the cells in MSC tumors are arranged in a papillary (i.e. finger-like) [17] or tubular [14] pattern. The extracellular microcysts and intracellular vacuoles and globules stain red when stained with the H&E stain, consist of sulfated glycosaminoglycans and mucin-containing material, [4] and are identified using periodic acid-Shiff, PAD diastase, or Alician blue stains. [15] The term “secretory” for MSC is in recognition that the tumor cells vacuoles and globules are secreted extracellularly to give the tissues their microcystic appearance. [8] At least 2 cases of MSC had sarcoma-like malignant cells in portions of their tumors and a rapidly metastasizing disease. [18] [19]
Immohistochemical analyses of MSC tumors detects cells that: in less than 50% of patients (including a male child [4] ) express estrogen and/or progesterone receptors; in rare cases express HER2/neu receptors; [14] and in most cases express S100 protein, mammaglobin protein, [17] and cytokeratin 5 or 6 (as detected using cytokeratin 5/6 antibodies). [16] In a study of 44 patients, MSC tumor cells expressed the estrogen receptor, progesterone receptor, HER2/Neu receptor, p53 tumor protein, and S100 protein in 21, 23, 16, 12, and 42 patients, respectively. [15]
MSC tumors carry a mutation, i.e. a balanced genetic translocation, in which part of the NTRK3 gene located in band two, five sub-band 2 (see chromosme banding) on the q (i.e. long) arm of chromosome 15 is fused to a part of the ETV6 gene located in band one, three sub-band 2 on chromosome 12. [14] The fusion gene product, ETV6-NTRK3, encodes a chimeric mutant protein, termed ETV6-NTRK3. [6] This fusion protein and its encoding ETV6-NTRK3 fusion gene are detected in the tumor cells of most (e.g. 88.6% [13] to 100% [8] ) cases of MSC. The NTRK3 portion of ETV6-NTRK3 protein has up-regulated tyrosine kinase activity. This activity stimulates two signaling pathways, the PI3K/AKT/mTOR and MAPK/ERK pathways, that promote cell proliferation, cell survival and, it is thought, thereby contribute to the development and/or progression of MSC. These pathways may also be responsible for stimulating the development of the vacuoles and globules seen in MSC tumors. [6] The ETV6-NTRK3 fusion gene and its ETV6-NTRK3 chimeric protein product are also detected in the tumor cells of mammary analogue secretory carcinoma of salivary glands, [20] [21] salivary gland–type carcinomas of the thyroid, [22] and secretory carcinoma of the skin. [12] This translocation is the sole genetic mutation reported in most MSC tumors; is a hallmark characteristic genetic abnormality in MSC tumor cells; [1] is used to confirm the diagnosis of MSC; [17] and has led to treating malignant MSC tumors with a drug, Larotrectinib, that inhibits the tyrosine kinase activity of the NTRK3 portion of the ETV6-NTRK3 fusion protein. [6]
The diagnosis of MSC tumors rests on their occurrence in breast ductal tissue, their distinct microscopic histopathological features [2] plus, particularly in tumors showing a papillary histopathology, [17] the presence of in the tumor of cells that express the ETV6-NTRK3 fusion gene and/or its ETV6-NTRK3 chimeric protein. [1] [15] [16] [17] While the ETV6-NTRK3 gene fusion occurs in many other tumor types (e.g. inflammatory myofibroblastic tumors, the cellular variant of congenital mesoblastic nephroma, and radiation-induced papillary thyroid carcinoma), these tumors' clinical presentations and histopathology findings distinguish them from MSC tumors. [13]
There have been no controlled studies that have evaluated the many different strategies that have been used to treat MSC tumors. [16] Studies have suggested that: 1) MSC tumor sizes less than 2 [13] or 3 [15] centimeters in widest dimension, tumors with circumscribed margins, tumors with no evidence of axillary lymph node metastasis, [15] tumors in individuals who are less than 20 [13] or 30 [14] years old at diagnosis, and/or tumors that are purely in situ [16] have more favorable prognoses; 2) MSC tumors with high rates of proliferation, tumors greater than 2 to 3 centimeters in widest dimension, [13] [15] tumors that contain areas of sarcoma-like cells, [19] tumors in individuals older than 20 or 30 years, [13] [14] and/or tumors that have spread to distant tissues [8] have less favorable prognoses.
In general, surgery has been considered the best treatment for MSC tumors but there is no consensus on the extent of this surgery. [15] Conservative surgery or simple mastectomy with biopsy of sentinel lymph nodes has been recommended for patients with MSC tumors that have more favorable prognoses. Removal of adjacent mammary tissue to the tumor to insure that all invasive tissue is removed has also been recommended since leaving tumor tissue behind after surgery runs a higher risk of local recurrences. [1] Tumors with unfavorable prognostic features have been treated with radical mastectomy. Since MSC tumors grow slowly, carry relatively good prognoses, and if metastasizing to distant tissues usually do so only 10 to 20 years after, [14] there is no strong evidence for the benefit of adjuvant chemotherapy and/or radiotherapy [4] A retrospective study of 190 patients with MSC that had not metastasized to distant tissue found that breast-conserving surgery plus radiotherapy gave significantly better survival times than simple mastectomy. [5] In general, conservative surgery, modified radical mastectomy, and radical mastectomy have been the most frequent procedures in adults while simple mastectomy, local excision with sentinel lymph node biopsy, and complete axillary dissection have been recommended as adequate treatment for children with MSC. [15] Further studies are needed to confirm that radiotherapy improves one or more of the latter treatment regimens. [5] In all cases, long-term follow-up examination, e.g. for at least 20 years after diagnoses, is strongly recommended. [1] [14]
The rare cases of MSC tumors that spread to distant tissues on their initial presentation or after prior treatment have been treated with various chemotherapy regimens. Responses to these regiments have been poor to nil. [8] [13] [14] Recently, three individuals (two juvenile females and one 26 year old male) with ETV6-NTRK3 fusion gene-harboring MSC tumors that metastasized to distant tissues were treated with Larotrectinib, a drug which attacks the genetic abnormality underlying this disease. The drug is an orally available selective NTRKi inhibitor that blocks the NTRK3 protein's tyrosine kinase activity. It has produced good, fast-developing responses in the three reported MSC cases. [6] [13] [16] However, these three responses were partial, i.e. some tumor tissue remained after treatment. [23] Further studies are needed on a much larger number of individuals with MSC to define the efficacy of Larotrectinib, the duration of its effects, and the efficacy of other MTRK3 protein inhibitors such as Entrectinib. [6] [23]
Overall, MSC has a favorable prognosis. [5] [23] A study of 190 individuals treated for MSC that had not spread to distant tissues reported survival rates (excluding individuals dying of other causes) at 5, 10, and 20 years after initial treatment of 95.79, 93.16, and 93.16%, respectively. [1] The uncommon cases of MSC which have metastasize to distant tissues may also have prolonged survival times [8] but some have proven to be fatal with shorter survival times (e.g. 1 year after diagnosis). [13] [15] [19] Larotrectinib therapy may improve the survival times in individuals with MSC tumors that have poorer prognoses. [23]
Mastectomy is the medical term for the surgical removal of one or both breasts, partially or completely. A mastectomy is usually carried out to treat breast cancer. In some cases, women believed to be at high risk of breast cancer have the operation as a preventive measure. Alternatively, some women can choose to have a wide local excision, also known as a lumpectomy, an operation in which a small volume of breast tissue containing the tumor and a surrounding margin of healthy tissue is removed to conserve the breast. Both mastectomy and lumpectomy are referred to as "local therapies" for breast cancer, targeting the area of the tumor, as opposed to systemic therapies, such as chemotherapy, hormonal therapy, or immunotherapy.
Breast cancer is a cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a red or scaly patch of skin. In those with distant spread of the disease, there may be bone pain, swollen lymph nodes, shortness of breath, or yellow skin.
Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, are metastases (mets). It is generally distinguished from cancer invasion, which is the direct extension and penetration by cancer cells into neighboring tissues.
Radical mastectomy is a surgical procedure that treats breast cancer by removing the breast and its underlying chest muscle, and lymph nodes of the axilla (armpit). Breast cancer is the most common cancer among women. During the early twentieth century it was primarily treated by surgery, when the mastectomy was developed. However, with the advancement of technology and surgical skills in recent years, mastectomies have become less invasive. As of 2016, a combination of radiotherapy and breast conserving mastectomy are considered optimal treatment.
ETV6 protein is a transcription factor that in humans is encoded by the ETV6 gene. The ETV6 protein regulates the development and growth of diverse cell types, particularly those of hematological tissues. However, its gene, ETV6 frequently suffers various mutations that lead to an array of potentially lethal cancers, i.e., ETV6 is a clinically significant proto-oncogene in that it can fuse with other genes to drive the development and/or progression of certain cancers. However, ETV6 is also an anti-oncogene or tumor suppressor gene in that mutations in it that encode for a truncated and therefore inactive protein are also associated with certain types of cancers.
Congenital mesoblastic nephroma, while rare, is the most common kidney neoplasm diagnosed in the first three months of life and accounts for 3-5% of all childhood renal neoplasms. It is generally non-aggressive and amenable to surgical removal, though there is a subtype that is more aggressive and tends to spread to other organs. Congenital mesoblastic nephroma was first named as such in 1967 but was recognized decades before this as fetal renal hamartoma or leiomyomatous renal hamartoma. It is embryologically derived from the metanephrogenic blastema, the same tissue that gives rise to nephroblastomatosis and Wilms tumor.
Breast cancer classification divides breast cancer into categories according to different schemes criteria and serving a different purpose. The major categories are the histopathological type, the grade of the tumor, the stage of the tumor, and the expression of proteins and genes. As knowledge of cancer cell biology develops these classifications are updated.
Male breast cancer (MBC) is a cancer in males that originates in their breasts. Males account for less than 1% of new breast cancers with about 20,000 new cases being diagnosed worldwide every year. Its incidence rates in males vs. females are, respectively, 0.4 and 66.7 per 100,000 person-years. The worldwide incidences of male as well as female breast cancers have been increasing over the last few decades. Currently, one of every 800 men are estimated to develop this cancer during their lifetimes.
Porocarcinoma (PCA) is a rare form of skin cancer that develops in eccrine sweat glands, i.e. the body's widely distributed major type of sweat glands, as opposed to the apocrine sweat glands which are located primarily in the armpits and perineal area. This cancer typically develops in individuals as a single cutaneous tumor in the intraepidermal spiral part of these sweat glands' ducts at or near to where they open on the skin's surface. PCA tumors are classified as one form of the cutaneous adnexal tumors; in a study of 2,205 cases, PCA was the most common (11.8%) form of these tumors.
Spiradenomas (SA) are rare, benign cutaneous adnexal tumors that may progress to become their malignant counterparts, i.e. spiradenocarcinomas (SAC). Cutaneous adnexal tumors are a group of skin tumors consisting of tissues that have differentiated towards one of the four primary adnexal structures found in normal skin: hair follicles, sebaceous sweat glands, apocrine sweat glands, and eccrine sweat glands. SA and SAC tumors were regarded as eccrine gland tumors and termed eccrine spiradenomas and eccrine spiradenocarcinomas, respectively. However, more recent studies have found them to be hair follicle tumors and commonly term them spiradenomas and spiradenocarcinomas, respectively. Further confusing the situation, SA-like and SAC-like tumors are also 1) manifestations of the inherited disorder, CYLD cutaneous syndrome (CCS), and 2) have repeatedly been confused with an entirely different tumor, adenoid cystic carcinomas of the salivary gland. Here, SA and SAC are strictly defined as sporadic hair follicle tumors that do not include the hereditary CCS spiradenomas and heridtary spiradenocarcinoms of CCS or the adenoid cystic carcinomas.
ETV6-NTRK3 gene fusion is the translocation of genetic material between the ETV6 gene located on the short arm of chromosome 12 at position p13.2 and the NTRK3 gene located on the long arm of chromosome 15 at position q25.3 to create the (12;15)(p13;q25) fusion gene, ETV6-NTRK3. This new gene consists of the 5' end of ETV6 fused to the 3' end of NTRK3. ETV6-NTRK3 therefore codes for a chimeric oncoprotein consisting of the helix-loop-helix (HLH) protein dimerization domain of the ETV6 protein fused to the tyrosine kinase domain of the NTRK3 protein. The ETV6 gene codes for the transcription factor protein, ETV6, which suppresses the expression of, and thereby regulates, various genes that in mice are required for normal hematopoiesis as well as the development and maintenance of the vascular network. NTRK3 codes for Tropomyosin receptor kinase C a NT-3 growth factor receptor cell surface protein that when bound to its growth factor ligand, neurotrophin-3, becomes an active tyrosine kinase that phosphorylates tyrosine residues on, and thereby stimulates, signaling proteins that promote the growth, survival, and proliferation of their parent cells. The tyrosine kinase of the ETV6-NTRK3 fusion protein is dysfunctional in that it is continuously active in phosphorylating tyrosine residues on, and thereby continuously stimulating, proteins that promote the growth, survival, and proliferation of their parent cells. In consequence, these cells take on malignant characteristics and are on the pathway of becoming cancerous. Indeed, the ETV6-NTRK3 fusion gene appears to be a critical driver of several types of cancers. It was originally identified in congenital fibrosarcoma and subsequently found in mammary secretory carcinoma, mammary analogue secretory carcinoma of salivary glands, salivary gland–type carcinoma of the thyroid, secretory carcinoma of the skin, congenital fibrosarcoma, congenital mesoblastic nephroma, rare cases of acute myelogenous leukemia, ALK-negative Inflammatory myofibroblastic tumour, cholangiocarcinoma, and radiation-induced papillary thyroid carcinoma.
Lymph node metastasis is the spread (metastasis) of cancer cells into a lymph node.
Mammary-type myofibroblastoma (MFB), also named mammary and extramammary myofibroblastoma, was first termed myofibrolastoma of the breast, or, more simply, either mammary myofibroblastoma (MMFB) or just myofibroblastoma. The change in this terminology occurred because the initial 1987 study and many subsequent studies found this tumor only in breast tissue. However, a 2001 study followed by numerous reports found tumors with the microscopic histopathology and other key features of mammary MFB in a wide range of organs and tissues. Further complicating the issue, early studies on MFB classified it as one of various types of spindle cell tumors that, except for MFB, were ill-defined. These other tumors, which have often been named interchangeably in different reports, are: myelofibroblastoma, benign spindle cell tumor, fibroma, spindle cell lipoma, myogenic stromal tumor, and solitary stromal tumor. Finally, studies suggest that spindle cell lipoma and cellular angiofibroma are variants of MFB. Here, the latter two tumors are tentatively classified as MFB variants but otherwise MFB is described as it is more strictly defined in most recent publications. The World Health Organization in 2020 classified mammary type myofibroblastoma tumors and myofibroblastoma tumors as separate tumor forms within the category of fibroblastic and myofibroblastic tumors.
Breast cancer metastatic mouse models are experimental approaches in which mice are genetically manipulated to develop a mammary tumor leading to distant focal lesions of mammary epithelium created by metastasis. Mammary cancers in mice can be caused by genetic mutations that have been identified in human cancer. This means models can be generated based upon molecular lesions consistent with the human disease.
Mammary analogue secretory carcinoma (MASC), also termed MASCSG, is a salivary gland neoplasm. It is a secretory carcinoma which shares the microscopic pathologic features with other types of secretory carcinomas including mammary secretory carcinoma, secretory carcinoma of the skin, and salivary gland–type carcinoma of the thyroid. MASCSG was first described by Skálová et al. in 2010. The authors of this report found a chromosome translocation in certain salivary gland tumors, i.e. a (12;15)(p13;q25) fusion gene mutation. The other secretory carcinoma types carry this fusion gene.
Low-grade myofibroblastic sarcoma (LGMS) is a subtype of the malignant sarcomas. As it is currently recognized, LGMS was first described as a rare, atypical myofibroblastic tumor by Mentzel et al. in 1998. Myofibroblastic sarcomas had been divided into low-grade myofibroblastic sarcomas, intermediate‐grade myofibroblasic sarcomas, i.e. IGMS, and high‐grade myofibroblasic sarcomas, i.e. HGMS based on their microscopic morphological, immunophenotypic, and malignancy features. LGMS and IGMS are now classified together by the World Health Organization (WHO), 2020, in the category of intermediate fibroblastic and myofibroblastic tumors. WHO, 2020, classifies HGMS as a soft tissue tumor in the category of tumors of uncertain differentiation. This article follows the WHO classification: here, LGMS includes IGMS but not HGMS which is a more aggressive and metastasizing tumor than LGMS and consists of cells of uncertain origin.
Secretory carcinoma was once used exclusively as a term for rare, slowly growing breast tumors without reference to their location in the breast. It is now termed mammary secretory carcinoma because secretory carcinoma has sometimes been used to name tumors which develop in non-breast tissues but have the microscopic appearance of, and a critical gene abnormality found in, mammary secretory carcinoma. This genetic abnormality is a balanced genetic translocation that forms a ETV6-NTRK3 fusion gene which appears involved in promoting the development and/or progression of all these tumors. The formerly termed secretory carcinomas include:
Papillary carcinomas of the breast (PCB), also termed malignant papillary carcinomas of the breast, are rare forms of the breast cancers. The World Health Organization (2019) classified papillary neoplasms of the breast into 5 types: intraductal papilloma, papillary ductal carcinoma in situ (PDCIS), encapsulated papillary carcinoma (EPC), solid-papillary carcinoma (SPC), and invasive papillary carcinoma (IPC). The latter four carcinomas are considered here; intraductal papilloma is a benign neoplasm. The World Health Organization regarded solid papillary carcinoma as having two subtypes: in situ and invasive SPC.
Invasive cribriform carcinoma of the breast (ICCB), also termed invasive cribriform carcinoma, is a rare type of breast cancer that accounts for 0.3% to 0.6% of all carcinomas in the breast. It originates in a lactiferous duct as opposed to the lobules that form the alveoli in the breasts' mammary glands. ICCB was first described by Dixon and colleagues in 1983 as a tumor that on microscopic histopathological inspection had a cribriform pattern, i.e. a tissue pattern consisting of numerous "Swiss cheese"-like open spaces and/or sieve-like small holes. The latest edition (2019) of the World Health Organization (2019) termed these lesions invasive cribriform carcinomas indicating that by definition they must have a component that invades out of their ducts of origin into adjacent tissues. In situ ductal cancers that have a cribriform histopathology are regarded as belonging to the group of ductal carcinoma in situ tumors.
Pure apocrine carcinoma of the breast (PACB) is a rare carcinoma derived from the epithelial cells in the lactiferous ducts of the mammary gland. The mammary gland is an apocrine gland. Its lactiferous ducts have two layers of epithelial cells, a luminal layer which faces the duct's lumen and a basal layer which lies beneath the luminal layer. There are at least four subtypes of epithelial cells in these ducts: luminal progenitor cells and luminal mature cells which reside in the luminal layer and mammary stem cells and basal cells which reside in the basal layer. Examination of the genes expressed in PACB cancer cells indicate that most of these tumors consist of cells derived from luminal cells but a minority of these tumors consist of cells derived from basal cells.