title: Lapatinib inhibits stem/progenitor proliferation in preclinical in vitro models of ductal carcinoma in situ (DCIS).
abstract: Breast-conserving surgery for ductal carcinoma in situ (DCIS) is often combined with irradiation, reducing recurrence rates to 20% within 10 years; however, there is no change in overall survival. Evidence in the invasive breast indicates that breast cancer stem cells (CSCs) are radiotherapy-resistant and are capable of re-initiating a tumor recurrence; hence, targeting CSCs in high risk DCIS patient may improve survival. HER2 is overexpressed in 20% of DCIS and is known to be highly active in breast CSCs; we therefore investigated the effect of Lapatinib on DCIS CSC activity using 2 in vitro culture systems. Two DCIS cell lines DCIS.com (HER2 normal) and SUM225 (HER2 overexpressed) as well as DCIS cells from patient samples (n = 18) were cultured as mammospheres to assess CSC activity and in differentiated 3D-matrigel culture to determine effects within the non-CSCs. Mammosphere formation was reduced regardless of HER2 status, although this was more marked within the HER2-positive samples. When grown as differentiated DCIS acini in 3D-matrigel culture, Lapatinib only reduced acini size in the HER2-positive samples via decreased proliferation. Further investigation revealed lapatinib did not reduce self-renewal activity in the CSC population, but their proliferation was decreased regardless of HER2 status. In conclusion we show Lapatinib can reduce DCIS CSC activity, suggesting that the use of Lapatinib in high-risk DCIS patients has the potential to reduce recurrence and the progression of DCIS to invasive disease.
authors.affiliation: Cancer Stem Cell Research; University of Manchester; Institute of Cancer Sciences; Manchester Academic Health Science Centre; Paterson Building; The Christie NHS Foundation Trust; Manchester, UK.
authors.forename: Gillian
authors.initials: G
authors.lastname: Farnie
authors.affiliation: Surgical Oncology; University Hospital of South Manchester NHS Foundation Trust; Wythenshawe Hospital; Manchester, UK.
authors.forename: Rachael L
authors.initials: RL
authors.lastname: Johnson
authors.affiliation: Cancer Stem Cell Research; University of Manchester; Institute of Cancer Sciences; Manchester Academic Health Science Centre; Paterson Building; The Christie NHS Foundation Trust; Manchester, UK; Surgical Oncology; University Hospital of South Manchester NHS Foundation Trust; Wythenshawe Hospital; Manchester, UK.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Williams
authors.affiliation: Breast Biology Group; University of Manchester; Institute of Cancer Sciences; Manchester Academic Health Science Centre; Paterson Building; The Christie NHS Foundation Trust; Manchester, UK.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Clarke
authors.affiliation: Surgical Oncology; University Hospital of South Manchester NHS Foundation Trust; Wythenshawe Hospital; Manchester, UK.
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Bundred
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D000077341:Lapatinib; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000187:drug effects*; D011799:Quinazolines / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D000077341:Lapatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases
keywords: DCIS; HER2; Lapatinib; cancer stem cells; proliferation